Arsenic Methylation Capacity, Methylenetetrahydrofolate Reductase and Dna Methylation Gene Polymorphisms, Plasma Selenium Concentration and Selenoprotein Gene Polymorphisms and Renal Cell Carcinoma

Our previous studies have well documented that the poor arsenic methylation capability was associated with an increased risk of urothelial carcinoma either in arseniasis endemic area or in non obvious arsenic exposure area. We found that urinary total arsenic was significantly associated with the odds ratio (OR) of renal cell carcinoma (RCC) in a dose-response relationship; the lower the estimated glomerular filtration rate (eGFR) and with hypertension was the higher OR of RCC in non obvious arsenic exposure area recently. In addition, we also found that subjects with the p53 Pro/Pro genotype or MDM2 SNP309 GG genotype had a significantly higher OR of RCC than those with the p53 Arg/Arg or MDM2 SNP309 TT genotypes; urinary 8-OHdG was significantly related to urinary total arsenic level, and urinary 8-OHdG was significantly associated with the increased OR of RCC in a dose-response relationship. However, the carcinogenic mechanism of RCC is still unclear. Therefore, the specific aims of this project are to explore the association among arsenic methylation capability, gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) and DNA methyltransferase, DNA hypermethylation, serum and urine selenium concentration and selenoprotein polymorphism, and RCC. This project is a three-year prospective study. We will use all study subjects recruited previously and they provided informed consents, and carried out questionnaire interview and their biospecimens including plasma, buffy coat, and urine were collected from non obvious arsenic exposure area, and their urinary arsenic species were determined already. We will continue to collect 150 RCC patients and 150 controls in next three years. First year we will use 392 RCC patients and 875 healthy controls recruited previously and 50 new RCC patients and new 50 controls to examine the polymorphism of MTHFR (C677T、A1298C、G1793A、rs9651118 and rs1476413) of subjects. In addition, we will examine the arsenic methylation capability of new RCC patients and controls. Second year we will continue to recruit new 50 RCC patients and 50 controls to examine the arsenic methylation capability and MTHFR polymorphism. In addition, we will analyze the polymorphism of DNA methyltransferase (DNMT1(rs2228611 and rs16999593), DNMT3A(rs13428812), DNMT3B(rs2424908 and rs2424913)) and DNA hypermethlation of p14、 p15 and p16 for all study subjects. Third year we will continue to recruit 50 RCC patients, and 50 controls to assay the arsenic methylation capability and the polymorphism of MTHFR and DNA methyltransferase, and DNA hypermethylation. We will also analyze the serum and urine selenium concentration and selenoprotein SEPP1 (rs3797310) and SEP15 (rs5859) polymorphism for all study subjects. This study will use external exposure dose, internal dose and susceptibility data to perform molecular epidemiology for examining arsenic methylation capability, polymorphism of MTHFR and DNA methyltrasferase, DNA hypermethylation of p14、p15 and p16, serum and urine selenium concentration and selenoprotein polymorphism on RCC risk. Finally, we will incorporate all external exposure dose, internal dose and susceptibility data to perform statistical analyses. We anticipate setting up and evaluating the arsenic methylation capability, polymorphism of MTHFR and DNA methyltrasferase, DNA hypermethylation of p14、 p15 and p16, serum and urine selenium concentration and selenoprotein polymorphism on RCC risk in non obvious arsenic exposure area. The findings from these three years projects are expected to publish in internationally prestigious journals.